title: Nebivolol attenuates prooxidant and profibrotic mechanisms involving TGF-β and MMPs, and decreases vascular remodeling in renovascular hypertension.
abstract: Nebivolol and metoprolol are β1-adrenergic receptor blockers with different properties. We hypothesized that nebivolol, but not metoprolol, could attenuate prooxidant and profibrotic mechanisms of hypertension and therefore protect against the vascular remodeling associated with hypertension. Hypertension was induced in male Wistar rats by clipping the left renal artery. Six weeks after surgery, hypertensive and sham rats were treated with nebivolol (10 mg kg(-1) day(-1)) or metoprolol (20 mg kg(-1) day(-1)) for 4 weeks. Systolic blood pressure was monitored weekly. Morphologic changes in the aortic wall were studied in hematoxylin/eosin and picrosirius red sections. Aortic NAD(P)H activity and superoxide production were evaluated by luminescence and dihydroethidium, respectively, and TBARS levels were measured in plasma. Aortic nitrotyrosine staining was evaluated to assess peroxynitrite formation. TGF-β levels and p-ERK 1/2 expression were determined by immunofluorescence and Western blotting, respectively. Matrix metalloproteinase (MMP) activity and expression were determined by in situ zymography, gel zymography, Western blotting, and immunofluorescence, and TIMP-1 was assessed by immunohistochemistry. Both β1-receptor antagonists exerted very similar antihypertensive effects. However, while metoprolol had no significant effects, nebivolol significantly attenuated vascular remodeling and collagen deposition associated with hypertension. Moreover, nebivolol, but not metoprolol, attenuated hypertension-induced increases in aortic NAD(P)H oxidase activity, superoxide production, TBARS concentrations, nitrotyrosine levels, TGF-β upregulation, and MMP-2 and -9 expression/activity. No effects on p-ERK 1/2 and TIMP-1 expression were found. These results show for the first time that nebivolol, but not metoprolol, attenuates prooxidant and profibrotic mechanisms involving TGF-β and MMP-2 and MMP-9, which promote vascular remodeling in hypertension.
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil.
authors.forename: Carla S
authors.initials: CS
authors.lastname: Ceron
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil.
authors.forename: Elen
authors.initials: E
authors.lastname: Rizzi
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil.
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Guimarães
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil.
authors.forename: Alisson
authors.initials: A
authors.lastname: Martins-Oliveira
authors.affiliation: Department of Morphology, Estomatology, and Physiology, Dental School of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP, Brazil, 14049-900.
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Gerlach
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil. Electronic address: tanus@fmrp.usp.br.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Tanus-Santos
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006978:Hypertension, Renovascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000187:drug effects / Q000378:metabolism; D000068577:Nebivolol; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000959:Antihypertensive Agents; D000975:Antioxidants; D001578:Benzopyrans; D004983:Ethanolamines; D016212:Transforming Growth Factor beta; D000068577:Nebivolol; D020782:Matrix Metalloproteinases
keywords: 2 kidney, one clip; 2K1C; DHE; ECM; ERK 1/2; MMP; Matrix metalloproteinases; Metoprolol; Nebivolol; Oxidative stress; Renovascular hypertension; SBP; TBARS; TGF; Vascular remodeling; dihydroethidium; extracellular matrix; extracellular regulated kinase 1/2; matrix metalloproteinase; systolic blood pressure; thiobarbituric acid-reactive substances; transforming grown factor